1. Field of the Invention
This invention provides new chemical compounds which are particular esters of the group of acids known as .beta.-lactam antibiotics including especially the penicillins and cephalosporins.
2. Description of the Prior Art
Many .beta.-lactam antibiotics have been converted to esters.
For examples in the area of penicillins of the ampicillin and amoxicillin type see U.S. Pat. No. 3,996,236, U.K. Pat. No. 1,488,308 and Farmdoc 81300T.
Some previous publications on penicillin esters are reviewed briefly in U.S. Pat. No. 3,996,236 as follows:
Esters of benzylpenicillins are disclosed in British Pat. No. 1,003,479 and U.S. Pat. No. 2,650,218, acyloxymethyl esters of ampicillin are discussed by W. V. Daehne et al. in J. Med. Chem., 13(4), 607-612 (1970). This publication also refers to early publications on the hydrolysis of esters. The pivaloyloxymethyl ester of ampicillin is also disclosed in U.S. Pat. Nos. 3,660,575 and 3,697,507. Various penicillin esters are also disclosed, for example, in U.S. Pat. No. 3,528,965 and U.K. Pat. No. 1,267,936. Various esters of 6-aminopenicillanic acid have been disclosed, for example, in U.S. Pat. Nos. 3,652,546 and 3,399,207. The crystalline toluene-p-sulphonate of the methoxymethyl ester of 6-aminopenicillanic acid was described by Jackson et al., Chemical Communications, 1970, pages 14-15. Methoxymethyl benzylpenicillinate and other penicillin esters are described by Jansen et al., J. Chem. Soc., 2127-32 (1965) and that publication refers to earlier publications such as Johnson, J. Amer. Chem. Soc., 75, 3636 (1953) and Barnden et al., J. Chem. Soc., 3733 (1953). The Jansen et al. publication is referred to in U.K. Pat. No. 1,217,143 published Dec. 31, 1970 (but not in the corresponding U.S. Pat. No. 2,650,218) in its generic disclosure on page 2 which names various specific esters of penicills, including methoxymethyl, and suggests acylation of those and other esters of 6-aminopenicillanic acid (6-APA) with "any of the acyl groups found in the side chains of known antibacterial penicillins, especially the group of" the formula for D-(-)-2-phenylglycine which occurs in ampicillin.
U.S. Pat. No. 3,714,146 discloses, inter alia, cephalexin and the compound having the formula ##STR1## which is the acetone adduct of cephalexin and is also called hetacephalexin.
U.S. Pat. No. 3,489,752 discloses, inter alia, cefadroxil and the compound having the formula ##STR2## which is the acetone adduct of cefadroxil and is also called hetacefadroxil. The specification contains the very general statement, "Also included are the easily hydrolyzed esters or amides of such acids which may be converted to the free acid form by chemical or enzymatic hydrolysis," but no such esters are exemplified or named.
The methoxymethyl esters of each of the compounds having the structures set forth immediately above have been disclosed in U.S. Pat. No. 4,125,716.
The prior art contains numerous patents and publications directed to the preparation of deacetoxy cephalosporins (3-methyl-.DELTA..sup.3 -cephems) by ring enlargement reactions of penicillin sulfoxides. Some of this art make general statements to the effect that substantially any known penicillin sidechain is suitable for use in the reaction. Alternatively, the art teaches that the resulting 3-methyl-.DELTA..sup.3 -cephem compound may be cleaved to produce 7-ADCA and then reacylated with substantially any sidechain. During the ring enlargement reaction the carboxyl group of the penicillin sulfoxide must be protected to prevent decarboxylation. This is often done by utilizing an ester of the penicillin sulfoxide--the product being the corresponding 3-methyl-.DELTA..sup.3 -cephem ester. Despite the voluminous prior art generated by numerous workers in this field, the instantly claimed compounds have not, to our knowledge, been described or disclosed in any of such prior art. The following are cited as more examples of broad disclosure patents in the ring enlargement field: Farmdoc 14260X; U.K. Pat. No. 1,430,944; U.S. Pat. Nos. 3,932,387 and 3,944,545.
In similar fashion there are many patents on new compounds or processes for making known compounds which contain broad disclosures with respect to .beta.-lactam antibiotics and/or esters thereof. The following list presents a casual sample:
______________________________________ Farmdoc 86586Y U.K. 1,315,566 Farmdoc 28688Y U.K. 1,341,449 Farmdoc 21182X U.K. 1,421,526, Farmdoc 14259X U.K. 1,425,571 Farmdoc 00144X Farmdoc 20401V Farmdoc 05417U Farmdoc 81607T U.S. Pat. No. 3,748,323 U.S. Pat. No. 3,885,233 U.S. Pat. No. 3,859,274 U.S. Pat. No. 3,862,004 U.S. Pat. No. 3,864,331 U.S. Pat. No. 3,873,519 U.S. Pat. No. 3,912,751 U.S. Pat. No. 3,931,405 U.S. Pat. No. 3,954,735 U.S. Pat. No. 4,012,518 ______________________________________
E. J. Corey et al., A New General Method for Protection of the Hydroxyl Function, Tetrahedron Letters, 11, 809-812 (1976) describe the preparation and use of methoxyethoxymethyl chloride (MEM chloride) to form ethers from alcohols.
.beta.-Methoxyethoxymethyl chloride (MEM chloride) is advertised for sale by Aldrich Chemical Company, Inc., 940 West Saint Paul Avenue, Milwaukee, Wisconsis 53233, U.S.A. for the protection of alcohols by formation of the corresponding ether which can be subsequently cleaved easily and specifically by Lewis acids and especially anhydrous ZnBr.sub.2 or TiCl.sub.4 in CH.sub.2 Cl.sub.2 solution at room temperature.
It was the object of the present invention to provide a derivative of orally absorbed cephalosporins and penicillins which would provide improved, that is, heightened or extended, blood levels or increased distribution into tissues upon oral administration compared to that of the parent antibiotic and, by comparison with the corresponding methoxymethyl esters, would exhibit greater stability to acids, would avoid the production of formaldehyde by metabolic breakdown and would avoid the use of carcinogenic reagents during their synthesis.